CD40 is a type I transmembrane protein of the tumor necrosis receptor superfamily. CD40 is an important molecule involved in B-cell proliferation and differentiation, immunoglobulin isotype switching, and cell viability. Receptor signaling is initiated by the binding of CD40 to the CD40 ligand (CD40L or CD154), which is primarily expressed on activated CD4+ T cells.
On normal cells, CD40 is expressed on cells with high proliferative potential, including hematopoietic progenitors, epithelial and endothelial cells, and all antigen-presenting cells (dendritic cells, activated B lymphocytes, and activated monocytes). CD40 is highly expressed on several types of B-cell hematologic malignancies including multiple myeloma, non-Hodgkin's lymphoma (NHL), and chronic lymphocytic leukemia (CLL). The high prevalence of CD40 expression on B-cell malignancies makes it an attractive potential tumor target for antibody-based cancer therapy. CD40 is also expressed on a majority of bladder cancers and a significant percentage of other solid tumors, including head and neck cancers, renal cell carcinomas, ovarian and lung cancer.
Anti-CD40 antibodies and their uses for treating B cell hematologic malignancies have been described. See, e.g., U.S. Pat. Nos. 6,946,129; 6,843,989; 6,838,261; WO 2000/075348; US-2002-0197256; WO 2006/128103; and WO 2007/075326. It has been shown that a humanized anti-CD40 antibody induces growth inhibition and apoptosis of CD40-positive cells in a subset of hematologic tumor cell lines through direct signal transduction. WO 2006/128103; WO 2007/075326. Furthermore, the humanized anti-CD40 antibody kills tumor cells via immune effector functions, including antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). In vivo, using xenograft models of multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL), the anti-CD40 antibody suppresses tumor growth and improves survival in severe combined immunodeficient (SCID) mice. Comparison of the anti-CD40 antibody to rituximab (Genentech, Inc.) in several models revealed anti-tumor activity of the anti-CD40 antibody was at least as effective as rituximab.
Seattle Genetics initiated Phase I clinical trials in 2004 with the humanized anti-CD40 antibody in a single agent multi-dose trial in patients with relapsed and refractory multiple myeloma (MM). Subsequently, Phase I trials were initiated in patients with relapsed non-Hodgkin's lymphoma (NHL) and chronic lymphocytic lymphoma (CLL). The results from these Phase I trials showed evidence for anti-tumor activity in myeloma patients with stable disease and decreased M-protein, NHL patients with partial and complete responses, and CLL patients with stable disease. A phase II trial of the anti-CD40 antibody in relapsed diffuse large B cell lymphoma (DLBCL) was initiated in December 2006.
Although it has been shown anti-CD40 antibodies can induce growth inhibition and apoptosis of CD40-positive cells and may have anti-tumor activity in various types of B cell lymphoma patients, not all B lymphoma cells are sensitive to anti-CD40 antibody mediated cell death. There remains a need to identify one or more predictive markers for the responsiveness of B-cell lymphoma patients to anti-CD40 antibody therapy.
All references cited herein, including patent applications and publications, are incorporated by reference in their entirety.